The antidepressant efficacy of the muscarinic antagonist scopolamine: Past findings and future directions.

Scopolamine is a nonselective muscarinic antagonist that has shown relatively rapid antidepressant effects, although to date the results are from limited clinical studies. Scopolamine reportedly has downstream signaling effects thought to be linked to neuroplasticity within glutamatergic synapses and consequent antidepressant action. In psychiatry, clinically validated pathways are unusual and thus merit further research in an effort develop more effect medicines for patients with mood disorders. Thus, we are faced with a unique opportunity to build on the clinical observation associated with scopolamine through reverse translation to identify of targets that retain the clinical efficacy while reducing the side effect profile. This chapter reviews the clinical antidepressant findings with scopolamine, including discussion of differential response across patient subgroups, as well as a review of biomarkers that predict clinical outcome. The preclinical data associated with scopolamine also are reviewed and convey a vision for narrowing in on the therapeutic muscarinic receptor subtype(s) that support the antidepressant effects to guide the development of next generation antimuscarinic drug targets for depression.